Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a non-sedating antihistamine useful for treating allergic reactions in animals including humans. See also Claritin brand of Loratadine. Product Information Sheet, dated 1/99. Desloratadine is disclosed in U.S. Pat. No. 4,659,716 as a non-sedating antihistamine.
Histamine H1-receptor antagonists are effective first-line therapeutic agents in the management of allergic rhinitis, a condition affecting approximately 45 million Americans with a trend toward a larger afflicted population. Due to the high incidence of allergic rhinitis across the full range of the population, antihistamines are often administered concurrently with other drugs. Because drug disposition and exposure can drastically change when a co-administered drug inhibits an avenue of elimination or disposition, e.g., a drug/drug interaction, the elevated exposure to one or more drugs can lead to potentially grave consequences.
Mammalian cells possess a natural battery of defense mechanisms against xenobiotic assault. A particular class of proteins actively transports an extensive array of structurally unrelated large lipophilic compounds from the cell, providing what is often known as multiple drug resistance (MDR). Multidrug resistance is characterized by active efflux or pumping of xenobiotics and pharmaceuticals via transmembrane proteins acting as hydrophobic xe2x80x9cvacuum cleaners.xe2x80x9d The protein product of the MDR1 gene encodes a 170 kD integral plasma membrane phosphorylated glycoprotein, P-glycoprotein (P-gp), which is the best known and most extensively studied among these transporters and thus far appears to have the largest substrate list. The gross structural features of P-gp appear to be shared by a large family of membrane transporters known as ATP-binding cassette (ABC) transporters, which evidently act as ATP-driven pumps that remove xenobiotics from the interior of cells. Expression of P-gp in normal human tissues, particularly within the cellular membranes of the gastrointestinal tract, liver, blood-brain barrier, adrenals, and kidneys, suggests that the protein plays a role in cellular protection as well as in secretion. While the primary function of this protein is unknown, its ability to confer resistance to a wide variety of structurally and chemically unrelated compounds remains impressive. Indeed, the substrate list for this transporter reveals that P-gp shares a similar tolerance or acceptance as cytochrome P450 3A4 (CYP3A4), the predominant intestinal and hepatic cytochrome P450 oxygenase enzyme, and may even prove to be more extensive in its substrate recognition and as an avenue of drug elimination.
Among the more grave examples of clinical drug interactions are the H1-receptor antagonist terfenadine with ketoconazole, as well as simvastatin with itraconazole and mibefradil; all are reportedly substrates/inhibitors of P-gp. Another H1-receptor antagonist, fexofenadine, also reportedly interacts with erythromycin and ketoconazole. A report implicates active transporters as a major factor in the disposition of fexofenadine. Cvetkovic M., et al., Drug Metab Dispos 1999, Aug;27(8):866-71. Additionally, P-gp polymorphisms may cause wide-ranging reactions to treatment with P-gp substrates. If a polymorphic gene product of MDR1 has inferior selectivity toward a therapy, increased systemic exposure to that erstwhile P-gp substrate could be expected. Decleves X., et al., Hum Mutat 15:486.
At therapeutically effective doses, desloratadine was surprisingly found to not detectably bind to the P-gp protein. Also, in clinical studies, desloratadine pharmacokinetics were minimally affected by coadministration of grapefruit juice, which is known to alter drug transporter function.
The molecular mechanism underlying the hepatic uptake of organic anions has been significantly elucidated. Meier, et al., Hepatology, 1997 26(6):1667-77. The organic anion transport polypeptide 1 (OATP1) is a Na+- and ATP-independent transporter localized to the basolateral membrane of hepatocytes (as well as cells in other tissues), where it plays a major role in uptake of a variety of structurally unrelated anionic, neutral, and even some cationic compounds from the blood into the cell. Ibid. OATP1 mediates uptake of a variety of amphipathic organic anions in exchange for HCO3 xe2x88x92 and/or GSH and has been detected in the cells of kidney, liver, brain, lung, and muscle tissue. OATP1 has been demonstrated to transport bromosulfophthalein (BSP), bile acids, anionic steroid conjugates, neutral steroids, and other drugs. The inhibition of OATP1 function results in decreased exposure of substrates to cytosol and hence tissue.
The human OATP uptake antiport transporter has been shown to effect the disposition of fexofenadine. Cvetkovic M, et al., Drug Metab Dispos 1999, Aug;27(8):866-71. This report shows results from cells transfected with an OATP clone given by the University Hospital, Zurich, Switzerland. Using monolayers of the transfected cells and parent cells as controls, the rate of uptake was measured over a range of [14C]fexofenadine concentrations. By analyzing the hyperbolic saturation curve a Km of 6.4xc2x12.2 xcexcM and a Vmax of 58 pmol/mg proteinxc2x7min was determined and this was an efficiency of transport ranking high among tested substrates. Ibid. Additionally, the researchers were able to show significant inhibition of fexofenadine uptake by the drugs ritonavir, saquinavir, and lovastatin, and some other drugs.
Many food constituents (polyphenols and flavonoids) can directly effect the function of this uptake transporter. It is known that grapefruit juice and a coumarin constituent of grapefruit juice can have an effect on human OATP1. Additionally, grapefruit juice at 5% inhibited about 90% of human OATP1 mediated fexofenadine uptake and a major coumarin constituent of grapefruit juice inhibited rat oatp1 with an IC50 less than 1 xcexcM. Dresser G. K., Drug Met Reviews, 2000, 32 (s2):193. This impedance can be predicted to cause clinical effects on fexofenadine.
As a substrate of transporters that is not metabolized by CYP enzymes, fexofenadine is commonly used as a probe of drug transporter function. In vitro and in vivo studies have shown that fexofenadine pharmacokinetics are dependent upon drug transporters: fexofenadine AUC is increase. 5- to 9-fold in mdr1 null (-l-) mice, which are devoid of P-gp activity. Murray, 2001 SCI-1124-01/EAS Abstract 4/01. Consequently, substances that alter the function of these transporters by decreasing or increasing their activity have the potential to alter the clinical safety and efficacy profiles of other P-gp/OATP substrates. Ibid.
Clinical studies have shown that consumption of such common foods as grapefruit juice, apple juice, and orange juice decrease fexofenadine AUC by 30% to 77%; inhibition of OATP-mediated drug uptake and/or induction of active drug efflux appears to be responsible. Ibid. Agents that modify P-gp/OATP activity-including St. John""s Wort, ketoconazole, and erythromycin, and terfenadine have also reportedly been shown in clinical trials to alter the bioavailability of fexofenadine. Ibid.
A recent clinical interaction study performed has produced a reduction in fexofenadine exposure when co-administered with grapefruit juice. In this four-way crossover study grapefruit juice reduced both Cmax and AUC of fexofenadine by 30%. Cohen A., et al., (Protocol No. P01380), SPRI Clinical Pharmacology Study, P01380. This result is consistent with the inhibition of OATP1 mediated uptake of fexofenadine since constituents in grapefruit are known to be potent inhibitors of this transporter. This result was corroborated and extended in a 5 way, cross-over study in which the reduction of fexofenadine bioavailability was also observed with orange, apple and grapefruit juice. Bailey D. G., et al., Clin Pharn Ther 2001 69(2):21 (Abs PI-82). Apples and oranges are known to contain various polyphenolics and flavonoids that inhibit some transporters. The mechanism of this effect on absorption was further elucidated by studies with mdr1a/1b-deficient (-l-) mice and in vitro with cells expressing heterologous rat Oatp3. The co-administration of grapefruit or orange juice with fexofenadine in the mdr knockout mice lacking P-gp reduced fexofenadine AUC. The Oatp3 in vitro experiments showed that fexofenadine is a substrate of this uptake transporter with a Km of 36 xcexcM. Since this transporter was shown to be inhibited by grapefruit juice, grapefruit constituents, and orange juice these observations indicate the importance of OATP uptake transport to the disposition of fexofenadine.
A further example that may exemplify the OATP transporter mechanism of interaction is the recently described suppressed exposure to fexofenadine when co-administered with rifampin. Hamman M. A., et al., Clin Pharmacol Ther2001 69(3):114-21. Fexofenadine Cmax was reduced about 35-50%; oral clearance is significantly increased. Although they did not determine the mechanism, it is probably inhibition of OATP function or induction of export transporter (ABC transporter). Rifampin is well known to induce (elevate production) xenobiotic enzymes, yet it is also an inhibitor of OATP1 and OATP2. This serves both as a further example supplementing those noted above, as well as a tool for further experiments.
The clinical effect of dietary salt on the bioavailability of fexofenadine deserves special study. Since dietary salt significantly lowers the AUC (xcx9c33%) and Cmax (xcx9c33%) of fexofenadine and OATP is driven by counter-transport of a small anion the observed effect might be mediated by this uptake transporter. Dresser, et al., Clin Pharm Ther 2001, 69 (2): 23 (Abs PI-88). Additionally, ABC transporter gene expression has been shown to be modulated by a high salt diet in rats. Another very intriguing clinical interaction is the suppressed exposure of fexofenadine caused by St. John""s Wort. Dresser, et al., Clin Pharm Ther 2001, 69 (2): 23 (Abs PI-90). Pre-administration of St. John""s Wort to 10 healthy volunteers also caused a dramatic decrease in fexofenadine AUC (xcx9c50%). Ibid. Since apple juice and other citrus fruit and St. John""s Wort both contain quercetin and chlorogenic acid, the OATP transporter, which is affected by various citrus constituents, deserves consideration as the potential mediator of this clinical interaction. However, another lab has observed a significant increase in fexofenadine Cmax after acute single dose (900 mg) of St. John""s Wort, but no significant effect after 14 days of dosing (300 mg). Hamman, MA., et al., Clin Pharmacol Ther2001 69(2):53 (Abs PII-83). This may be caused by inhibition of an efflux transporter (ABC transporter) at the single acute dose and competing effects at the chronic dose.
In summary, the OATP uptake transporters are believed to be critical to fexofenadine disposition and bioavailabilty. Furthermore, the many other diverse substrates are causing decreased exposure of fexofenadine via this recently appreciated active transporter.
Potential drug interactions with fexofenadine via this avenue (OATP1) could include such commonly used pharmaceuticals as lovastatin, atorvastatin, simvastatin, saquinavir, ritonavir, quinidine, Cvetkovic M., et al., Drug Metab Dispos 1999, Aug;27(8):866-71, and pravastatin, Hsiang B., et al., J Biol Chem 1999, 274(52):37161-37168. Interactions would also likely be possible with corticosterone, Kanai N., et al., Am J Physiol 1996, 270(2):F319-325, dexamethasone, cortisol and aldosterone, Bossuyt X., et al., JPET 1996, 276:891-896, dehydroepiandrosterone, Kullak-Ublick G-A, , et al., FEBS Lett 1998 424:173-176, ibuprofen, Kouzuki H., et al., JPET 1999 288:627-634, indomethacin, Kouzuki, H , et al., JPET 2000 292:505-511, APD-ajmalinium (cationic derivative of the antiarrhythmic compound N-propylajmaline), Bossuyt X., et al, JPET 1996, 276:891-896.; and Meier, et al, Hepatology, 1997 26(6):1667-77, peptidomimetics and many others, Meier, et al., Hepatology, 1997 26(6):1667-77.
Persuasive in vitro evidence for a selective mechanism of interaction has been reported for some of these compounds. Pravastatin reportedly significantly interacts with rat OATP1 and simvastatin, lovastatin, and atorvastatin reportedly effectively inhibit rat OATP1 at 50 xcexcM. Rat OATP1 reportedly minimally affects ibuprofen uptake. Corticosterone sulfate reportedly effectively inhibits rat OATP1 at 10 xcexcM (some other steroids include: dehydroepiandrosterone and aldosterone). Ritonavir and saquinavir (HIV therapy protease inhibitors) reportedly effectively inhibit human OATP1 at 10 xcexcM. Lovastatin reportedly effectively inhibits human OATP1 at 10 xcexcM. Quinidine reportedly moderately inhibits human OATP1 at 10 xcexcM and strongly at 100 xcexcM. Of note, human OATP2 reportedly interacts with all of the statins. Additionally, rat OATP reportedly transports APD-ajmalinium, a permanently cationic derivative of the antiarrhythmic compound N-propylajmaline. Of these, lovastatin, saquinavir, ritonavir, and corticosterone (possibly, quinidine, APD-ajmalinium or pravastatin) should be most likely to result in a clinically significant drug interaction.
Drug transporters can have complex effects on the bioavailability of even negligibly metabolized drugs. Accordingly, there exists a need for a method of treating allergic and inflammatory conditions while avoiding the potential concomitant interaction with the OATP and P-gp enzyme systems.
Accordingly, there is disclosed a method treating and/or preventing allergic and inflammatory conditions of the skin or airway passages in a human in need of such treating and/or preventing which comprises administering to said human an effective amount of a nonsedating antihistamine for such treating and/or preventing while avoiding the side effects associated with other nonsedating antihistamines that bind to the P-glycoprotein pump and/or the organic anion transport polypeptide pump.
Also disclosed is a method treating and/or preventing allergic and inflammatory conditions of the skin or airway passages in a human of 12 years and older in need of such treating and/or preventing which comprises administering to said human an effective amount of a nonsedating antihistamine sufficient for such treating and/or preventing in the absence of the side effects associated with other nonsedating antihistamines that bind to the P-glycoprotein pump or the organic anion transport polypeptide pump.
Also disclosed is a method of treating and/or preventing seasonal or perennial allergic rhinitis in a human in need of such treating and/or preventing which comprises administering to said human an effective amount of desloratadine for such treating and/or preventing while avoiding the side effects associated with other nonsedating antihistamines that bind to the P-glycoprotein pump and/or the organic anion transport polypeptide pump.
Also disclosed is a method of treating and/or preventing atopic dermatitis or urticaria in a human in need of such treating and/or preventing which comprises administering to said human an effective amount of desloratadine for such treating and/or preventing while avoiding the side effects associated with other nonsedating antihistamines that bind to the P-glycoprotein pump and/or the organic anion transport polypeptide pump.
Also disclosed is a method of treating and/or preventing allergic asthma in a human in need of such treating and/or preventing which comprises administering to said human an effective amount of desloratadine for such treating and/or preventing while avoiding the side effects associated with other nonsedating antihistamines that bind to the P-glycoprotein pump and/or the organic anion transport polypeptide pump.